U.va. Professor Looks For Schizophrenia Cause

Research Points To Maternal Link

CHARLOTTESVILLE — Richard Applegate recalls leaving out bits of bread and butter for the fairies who often visited him.

"They never ate any of it, though," he notes with a hearty laugh.

For months Applegate believed it was his mission to care for the tiny creatures, whom he refers to as "the micro- people."

"They were the race of people that have been or might have been," the 44-year-old Charlottesville resident explained. "They came to me because I don't have any children. They could fly through the sky and leap to other planets," he said. "They were real cute."

Applegate was diagnosed as having schizophrenia in 1975. He's one of an estimated 1.8 million nationwide.

The condition is considered by many psychiatrists to be one of the most destructive mental illnesses. It essentially scrambles the senses, tormenting a person with delusions and auditory and visual hallucinations.

"In the face of incredible dysfunction, there's been very little to see. There are so few clues as to why it's happening," said Dr. W. Davis Parker, a University of Virginia professor of neurology who's conducting research into the cause of schizophrenia.

"It's not like degenerative diseases, where the brain changes in a visible way," Parker said. "With Alzheimer's, there's a loss of brain cells, there's all kinds of things that you can see in an autopsy. With schizophrenia, there's none of that."

Parker is determined to unravel this mystery. He's working to find answers -- answers to questions about how it's caused, how to definitively diagnose it and how to best treat it.

"Right now there's no lab test to tell if someone has schizophrenia. We go by clinical impression based on the patient's symptoms," said Dr. Russel H. Swerdlow, a U.Va. assistant professor of neurology and a colleague of Parker's.

But the U.Va. research offers hope.

"If sequencing data confirms Parker's hypothesis, it would allow us to develop a blood test that would help us diagnosis schizophrenia accurately," Swerdlow said. "And by targeting the genetic defects, we'd be better able to develop new treatments."

Parker believes people inherit schizophrenia from their mothers -- a radical departure from the prevailing theory, which posits that it can be passed down from either parent.

Parker's theory, which asserts the disorder is passed on through defects in maternally inherited mitochondrial DNA, has been bolstered by research he recently presented to the Society for Neuroscience at its annual conference in San Diego.

The experiment conducted by Parker and his six-person U.Va. team worked like this:

First, they extracted healthy mitochondrial DNA from cells and replaced it with mitochondrial DNA from people with schizophrenia. The mitochondria is the part of a cell where energy is created.

Then they watched to see if the DNA from people with schizophrenia altered, in any way, the cell's normal functioning.

It did.

"We've found it affects cells in ways that could cause a physiologic disorder," Swerdlow said. "We now have data to express that mitochondrial DNA is abnormal in people with schizophrenia."

Parker's research also has found that many of the drugs that treat schizophrenia affect mitochondria.

"Right now there's some debate on how these drugs work. But it's clear they do work," Parker said. "The hope is that if we know exactly what's wrong, we might design more effective drugs with fewer side effects."

Parker began his schizophrenia research in 1998 with the help of U.Va. graduate student Daniel Binder.

At that time, Parker suspected mitochondrial DNA might cause schizophrenia because of the way the disease manifests itself in families.

The dominant theory about the cause of schizophrenia asserts that the disease is passed from one generation to another by nuclear -- not mitochondrial -- DNA.

But if a disease were passed by way of nuclear DNA, then it would follow dominant and recessive patterns -- meaning doctors could predict with some reliability when it would show up.

Schizophrenia, significantly, cannot be so easily predicted.

"Schizophrenia does not behave like known genetic disorders. This leaves some researchers looking for nongenetic answers," Parker said.